Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology

Abstract

The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3–7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10–14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology. In a genome-wide association study for traits related to pancreatic beta-cell function in 26,000 individuals, 55 independent associations mapping to 44 genetic loci are identified.